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Novel Classes of Antibiotics or More of The Same?: Review
Novel Classes of Antibiotics or More of The Same?: Review
Novel Classes of Antibiotics or More of The Same?: Review
BJP Pharmacology
www.brjpharmacol.org
The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed.
Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant
bacteria until 10–20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance,
particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public
domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in
Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the
current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the
world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of
bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20
classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives
could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by
governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to
re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this
effort. The alternative is Medicine without effective antibiotics.
LINKED ARTICLES
This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit
http://dx.doi.org/10.1111/bph.2011.163.issue-1
Abbreviations
DNA, deoxyribonucleic acid; HAP, Hospital acquired pneumonia; HIV/AIDS, human immunodeficiency/ acquired
immunodeficiency syndrome; MRSA, methicillin resistant Staphylococcus aureus; RNA, ribonucleic acide; spp, species; TB,
tuberculosis; VAP Ventilator associated pneumonia
184 British Journal of Pharmacology (2011) 163 184–194 © 2011 The Authors
British Journal of Pharmacology © 2011 The British Pharmacological Society
New antibiotic classes are urgently needed
BJP
New Classes tially over the past two to three decades; now, only five
remain active in the field (Boucher et al., 2009). Governments
Marketed Needed
did not increase funding for antibiotic discovery, including
education in this field, fast enough to cope with the rise in
antibiotic resistance (House of Lords, 1998). This is a major
[-----20-----] [--2--] [-------------20?-----------][----------- 20?----------------] concern for many countries. Meanwhile, regulatory require-
ments increased, which has elevated the costs of developing
Year:
drugs, and the profits from competing products led pharma-
ceutical companies away from the antibiotic field.
1940—50—60—70—80—90—2000—10—20—30—40—50—60—70—80—90—2100—10
Class examples
b-Lactams
Penicillins
Penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin,
mezlocillin, piperacillin, azlocillin, temocillin
Cephalosporins
First generation Cephalothin, cephapirin, cephradine, cephaloridine, cefazolin
Second generation Cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefmetazole
Third generation Cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir
Fourth generation Cefpirome, cefepime
Fifth generation1 Ceftaroline2, ceftobiprole3
Carbapenems
Imipenem, meropenem, doripenem
Monobactams
Aztreonam
b-Lactamase inhibitors
Clavulanate, sulbactam, tazobactam
Aminoglycosides
Streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin,
isepamicin
Tetracyclines
Tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline, tigecycline
Rifamycins
Rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin, rifaximin
Macrolides
Erythromycin, azithromycin, clarithromycin
Ketolides
Telithromycin
Lincosamides
Lincomycin, clindamycin
Glycopeptides
Vancomycin, teicoplanin, telavancin
Lipopeptides
Daptomycin
Streptogramins
Quinupristin, dalfopristin, pristinamycin
Sulphonamides
Sulphanilamide, para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfathalidine
Oxazolidinones
Linezolid
Quinolones
Nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin/levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin,
fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin
Others
Metronidazole, polymyxin B, colistin, trimethoprim
1
Spectrum combines third generation gram-negatives with methicillin resistant Staphylococcus aureus (MRSA) and multidrug-resistant
Streptococcus pneumoniae.
2
Pending Federal Drugs Administration review.
3
Marketed in Canada and Switzerland; now withdrawn.
Glycopeptide Dalbavancin Gram-positive (excluding VRE) IV; once-weekly cSSTI Phase III Durata Therapeutics
(Pfizer)
Glycopeptide Telavancin Gram-positive (excluding VRE) IV cSSTI and HAP Marketed for SSTI in Astellas (Theravance)
USA; HAP approval
ARM Coates et al.
stalled at FDA
Glycopeptide Oritavancin Gram-positive (including VRE) IV; single dose cSSTI Phase III The Medicines
treatment Company (Lilly)
Cephalosporin Ceftaroline Gram-positive and gram-negative IV SSTI, CAP Pre-registration Forest (Cerexa)
excluding ESBLs etc. and
non-fermenters
Glycopeptide- TD-1792 Gram-positive IV SSTI, HAP Phase IIa Theravance
cephalosporin hybrid
Ketolide Cethromycin Gram-positive and respiratory tract Oral and IV Community-acquired RTIs Phase III Advanced Life Sciences
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